Friedman E, Cooper T B, Dallob A
Eur J Pharmacol. 1983 Apr 22;89(1-2):69-76. doi: 10.1016/0014-2999(83)90609-x.
The effect of acute and chronic treatments with conventional and atypical antidepressant drugs on serotonin receptor activity was assessed by the responsiveness of mice to the serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine. Acute treatment with 10 mg/kg of amitriptyline, imipramine, trazodone, mianserin or viloxazine reduced the head twitch response measured 1 h following a challenged dose of the serotonin agonist. Acute iprindole and desmethylimipramine, however, had no effect on the serotonergic response. Chronic treatment with the clinically effective antidepressants amitriptyline, imipramine, desmethylimipramine, iprindole, and trazodone produced an enhanced responsiveness to 5-MeODMT. The enhanced responsiveness was first observed 24 h after cessation of treatment with most drugs. The effect lasted for at least 48 h. Chronic treatment with the neuroleptic haloperidol did not result in altered responsivity to the serotonin agonist. Brain accumulation of imipramine and amitriptyline and their deaminated metabolites were measured. Brain drug and metabolite levels peaked 1 h following both acute and chronic treatments. Brain accumulations of amitriptyline and its metabolite were much greater than those of imipramine and its metabolite. This pharmacokinetic data is consistent with an early (1 h) antagonism of the 5-MeODMT response and the emergence of hightened responsiveness to 5-MeODMT after chronic treatment, when brain drug levels are reduced. These findings are also consistent with the greater inhibitory effect found after treatment with amitriptyline than with imipramine. It is concluded that enhanced serotonin neurotransmission which develops during chronic treatment with antidepressant drugs may be related to the clinical action of these drugs.
通过小鼠对5-甲氧基-N，N-二甲基色胺（5-methoxy-N,N-dimethyltryptamine）这种5-羟色胺受体激动剂的反应性，评估了传统和非典型抗抑郁药物的急性和慢性治疗对5-羟色胺受体活性的影响。用10mg/kg的阿米替林、丙咪嗪、曲唑酮、米安色林或维洛沙嗪进行急性治疗，可降低在给予5-羟色胺激动剂激发剂量后1小时测得的头部抽搐反应。然而，急性给予伊普吲哚和去甲丙咪嗪对5-羟色胺能反应没有影响。用临床有效的抗抑郁药物阿米替林、丙咪嗪、去甲丙咪嗪、伊普吲哚和曲唑酮进行慢性治疗，可增强对5-甲氧基-N，N-二甲基色胺（5-MeODMT）的反应性。大多数药物在停止治疗24小时后首次观察到反应性增强。这种作用持续至少48小时。用抗精神病药物氟哌啶醇进行慢性治疗不会导致对5-羟色胺激动剂的反应性改变。测定了丙咪嗪和阿米替林及其脱氨基代谢产物在脑中的蓄积情况。急性和慢性治疗后1小时，脑中药物和代谢产物水平均达到峰值。阿米替林及其代谢产物在脑中的蓄积量远大于丙咪嗪及其代谢产物。这些药代动力学数据与急性治疗时（1小时）对5-甲氧基-N，N-二甲基色胺（5-MeODMT）反应的拮抗作用以及慢性治疗后脑药物水平降低时对5-甲氧基-N，N-二甲基色胺（5-MeODMT）反应性增强的出现相一致。这些发现也与阿米替林治疗后比丙咪嗪治疗后具有更大抑制作用的结果相一致。得出的结论是，抗抑郁药物慢性治疗期间出现的5-羟色胺神经传递增强可能与这些药物的临床作用有关。
